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WO2021222069A1 - Méthodes et compositions pour le traitement d'infections de type choc cytokinique, notamment la covd-19, par inhibition de l'interaction ccr5/ccl5 - Google Patents

Méthodes et compositions pour le traitement d'infections de type choc cytokinique, notamment la covd-19, par inhibition de l'interaction ccr5/ccl5 Download PDF

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WO2021222069A1
WO2021222069A1 PCT/US2021/029096 US2021029096W WO2021222069A1 WO 2021222069 A1 WO2021222069 A1 WO 2021222069A1 US 2021029096 W US2021029096 W US 2021029096W WO 2021222069 A1 WO2021222069 A1 WO 2021222069A1
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ccr5
ccl5
methyl
subject
rantes
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Edgar B. Francisco
Hallison Rodrigues
Amruta Pise
Bruce K. Patterson
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IncellDx Inc
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IncellDx Inc
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Priority to EP21797089.6A priority Critical patent/EP4143235A4/fr
Priority to PH1/2021/551739A priority patent/PH12021551739A1/en
Priority to BR112021012654A priority patent/BR112021012654A2/pt
Publication of WO2021222069A1 publication Critical patent/WO2021222069A1/fr
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    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
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    • C07K14/521—Chemokines
    • C07K14/523—Beta-chemokines, e.g. RANTES, I-309/TCA-3, MIP-1alpha, MIP-1beta/ACT-2/LD78/SCIF, MCP-1/MCAF, MCP-2, MCP-3, LDCF-1, LDCF-2
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    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
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Definitions

  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 was first reported in December 2019. Since the initial cases of COVID- 19 were reported from Wuhan, China in December 2019 (Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497-506 (2020)), SARS-CoV-2 has emerged as a global pandemic with an ever-increasing number of severe cases requiring invasive external ventilation that threatens to overwhelm health care systems (World Health Organization. Coronavirus disease (COVID-2019) situation reports.
  • SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
  • CCR5 blockade using small molecule inhibitors or humanized monoclonal antibodies has been therapeutically deployed to protect certain critical immune cells populations, such as memory CD4 T-cells and monocytes/macrophages that express CCR5, from being infected.
  • CCR5 and its ligand CCL5 are also important in a host of other diverse diseases, such as non-alcoholic steatohepatitis (NASH), graft versus host disease (GvHD), and cancer, the effects of CCR5 blockade have been extensively investigated.
  • CCL5 is produced by both tumor cells but more importantly in CD3+ lymphocytes in the tumor microenvironment (TME) which are brought in by CXCL9 and CXCL10 which are produced by CD68+ myeloid cells.
  • CCL5 causes further migration of macrophages and other immune cells into the TME where they produce anti-tumor pro-inflammatory cytokines.
  • CCR5 blockade breaks this cycle by repolarizing macrophages from a pro-tumor M2 phenotype to an anti-tumor M1 phenotype.
  • CCR5 blockade blocks the influx of regulatory T-cells that express CCR5 and inhibit both the innate and cell-mediated immune responses that function both in cancer immunology and viral infections.
  • FIGS.1A-1D provide the extent and phenotype of cytokines and chemokines involved in hypercytokinemia in critical COVID-19.
  • cytokines/chemokines were tested in plasma from ten COVID-19 patients at Day 0, Day 3 and Day 7 post-leronlimab therapy. All cytokines/chemokines were extremely variable at Day 0 in the 10 critical patients including the IL- 1b, IL-6, and IL-8 which are commonly associated with the cytokine storm. Conversely, CCL5/RANTES was significantly elevated in all patients. Seven days post-leronlimab, IL-6 dropped dramatically. Though CCL5/RANTES did not drop as abruptly, blockade of CCR5 by leronlimab as determined by receptor occupancy was close to 100% at day 7 in all patients.
  • a disease refers to the risk posed by the disease to a subject. Severity of a disease also dictates the extent of treatment necessary for appropriately treating the subject. For example, a disease can be mild, moderate, severe, or critical. A mild disease may cause slight discomfort and may resolve without any treatment, for example, where a subject’s immune system neutralizes the disease. A moderate disease may cause more than slight discomfort and may require some treatment for the disease to resolve. A severe disease causes significant discomfort and would require extensive treatment. A critical disease is life threatening and would require hospitalization and extensive treatment, which may not be successful resulting in the subject’s death. Acute respiratory distress syndrome (ARDS) is a respiratory failure caused by rapid and widespread inflammation in the lungs.
  • ARDS acute respiratory distress syndrome
  • SIRS Systemic inflammatory response syndrome
  • specific binding refers to a direct association between two molecules, due to, for example, covalent, electrostatic, hydrophobic, and ionic and/or hydrogen-bond interactions, including interactions such as salt bridges and water bridges.
  • a specific binding member describes a member of a pair of molecules which have binding specificity for one another.
  • the members of a specific binding pair may be naturally derived or wholly or partially synthetically produced.
  • One member of the pair of molecules has an area on its surface, or a cavity, which specifically binds to and is therefore complementary to a particular spatial and polar organization of the other member of the pair of molecules.
  • the members of the pair have the property of binding specifically to each other.
  • pairs of specific binding members are antigen- antibody, biotin-avidin, hormone-hormone receptor, receptor-ligand, enzyme-substrate.
  • Specific binding members of a binding pair exhibit high affinity and binding specificity for binding with the each other.
  • affinity between the specific binding members of a pair is characterized by a K d (dissociation constant) of 10 -6 M or less, such as 10 -7 M or less, including 10 -8 M or less, e.g., 10 -9 M or less, 10 -10 M or less, 10 -11 M or less, 10 -12 M or less, 10 -13 M or less, 10 -14 M or less, including 10 -15 M or less.
  • Methods of treating a subject suffering from COVID-19 are provided. Aspects of the methods including administering to the subject an effective amount of an inhibitor of CCR5/CCL5 interaction, such as a CCR5 antagonist. Also provided are methods of assessing severity of a disease involving hypercytokinemia, such as COVID-19, by determining the level of CCL5/RANTES in a subject, as well as compositions for use in such methods. The disclosure identifies the role of the CCL5/RANTES in the severity of a disease involving hypercytokinemia, particularly, overproduction of immune cells and pro-inflammatory cytokines into the lungs of a subject.
  • an increased level of CCL5/RANTES indicates a more severe form of a disease
  • a level of CCL5/RANTES comparable to controls indicates a mild form of a disease.
  • certain embodiments of the invention provide a method of assessing the severity of a disease involving hypercytokinemia by determining the level of CCL5/RANTES in a subject.
  • Certain embodiments also provide methods of treating a disease involving hypercytokinemia in a subject by administering an inhibitor of CCL5/RANTES or an inhibitor of CCR5 to the subject having, relative to controls, an increased level of CCL5/RANTES.
  • FIG. 1 For purposes of this invention, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
  • aspects of the invention include methods of treating a subject suffering from a hypercytokinemia disease, such as COVID-19.
  • a hypercytokinemia disease such as COVID-19.
  • the terms "subject,” “individual,” “host,” and “patient,” are used interchangeably herein and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans.
  • treatment it is meant that at least an amelioration of one or more symptoms associated with the condition afflicting the subject is achieved, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g., a symptom associated with the impairment being treated.
  • treatment also includes situations where a pathological condition, or at least symptoms associated therewith, are completely inhibited, e.g., prevented from happening, or stopped, e.g., terminated, such that the adult mammal no longer suffers from the impairment, or at least the symptoms that characterize the impairment.
  • treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease.
  • Treatment may be any treatment of a disease in a mammal, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; or (c) relieving the disease, i.e., causing regression of the disease. Treatment may result in a variety of different physical manifestations, e.g., rejuvenation of tissue or organs, changes in cytokine levels, etc. Treatment of ongoing disease, where the treatment stabilizes or reduces the undesirable clinical symptoms of the patient, occurs in some embodiments.
  • hypercytokinemia disease is meant a disease condition that is characterized by the presence of hypercytokinemia (also known as a cytokine storm).
  • hypercytokinemia refers to a severe immune reaction in which the body releases too many cytokines into the blood too quickly. Cytokines play an important role in normal immune responses, but having a large amount of them released in the body all at once can be harmful. Hypercytokinemia can occur as a result of an infection, autoimmune condition, or other disease. It may also occur after treatment with some types of immunotherapy.
  • hypercytokinemia diseases may be caused by a viral infection.
  • the hypercytokinemia disease that is treated by methods of the invention is COVID-19, which is caused by SARS-CoV-2 infection.
  • the disease e.g., COVID-19, is severe or critical.
  • aspects of the methods of these embodiments include administering to a subject an active agent that inhibits CCR5 mediated CCL5 signaling, such as an inhibitor of CCR5/CCL5 binding interaction.
  • any convenient active agent may be employed, where active agents include, but are not limited to, CCR5 antagonists/inhibitors, CCL5 antagonists/inhibitors, etc.
  • any convenient type of active agent may be employed, where examples of active agent types include, but are not limited to: small molecules, nucleic acids, specific binding member for CCR5 or CCL5, such as, but not limited to, antibodies, aptamers, peptides, etc.
  • the active agent is a small molecule agent that exhibits the desired activity.
  • Naturally occurring or synthetic small molecule compounds of interest include numerous chemical classes, such as organic molecules, e.g., small organic compounds having a molecular weight of more than 50 and less than about 2,500 Daltons.
  • Candidate agents comprise functional groups for structural interaction with proteins, particularly hydrogen bonding, and typically include at least an amine, carbonyl, hydroxyl or carboxyl group, preferably at least two of the functional chemical groups.
  • the candidate agents may include cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups.
  • Candidate agents are also found among biomolecules including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs or combinations thereof. Such molecules may be identified, among other ways, by employing the screening protocols described below.
  • the active agent is a protein or fragment thereof or a protein complex.
  • the active agent is an antibody binding agent or derivative thereof.
  • antibody binding agent includes polyclonal or monoclonal antibodies or fragments, that are sufficient to bind to an analyte of interest, e.g., CCR5 or CCL5.
  • the antibody fragments can be, for example, monomeric Fab fragments, monomeric Fab' fragments, or dimeric F(ab)'2 fragments.
  • antibody binding agent molecules produced by antibody engineering, such as single-chain antibody molecules (scFv) or humanized or chimeric antibodies produced from monoclonal antibodies by replacement of the constant regions of the heavy and light chains to produce chimeric antibodies or replacement of both the constant regions and the framework portions of the variable regions to produce humanized antibodies.
  • the active agent is an enzyme or enzyme complex.
  • the active includes a phosphorylating enzyme, e.g., a kinase.
  • the active is a complex including a guide RNA and a CRISPR effector protein, e.g., Cas9, used for targeted cleavage of a nucleic acid.
  • the active agent is a nucleic acid.
  • the nucleic acids may include DNA or RNA molecules.
  • the nucleic acids modulate, e.g., inhibit or reduce, the activity of a gene or protein, e.g., by reducing or downregulating the expression of the gene.
  • the nucleic acid may be a single stranded or double-stranded and may include modified or unmodified nucleotides or non-nucleotides or various mixtures and combinations thereof.
  • the active agent includes intracellular gene silencing molecules by way of RNA splicing and molecules that provide an antisense oligonucleotide effect or a RNA interference (RNAi) effect useful for inhibiting gene function.
  • RNAi RNA interference
  • gene silencing molecules such as, e.g., antisense RNA, short temporary RNA (stRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), tiny non- coding RNA (tncRNA), snRNA, snoRNA, and other RNAi-like small RNA constructs, may be used to target a protein-coding as well as non-protein-coding genes.
  • the nucleic acids include aptamers (e.g., aptamers).
  • the nucleic acids include antisense compounds.
  • the nucleic acids include molecules which may be utilized in RNA interference (RNAi) such as double stranded RNA including small interfering RNA (siRNA), locked nucleic acid (LNA) inhibitors, peptide nucleic acid (PNA) inhibitors, etc.
  • RNAi RNA interference
  • the active agent employed in embodiments of methods of the invention is a CCR5 targeting agent, such as a CCR5 inhibitor/antagonist.
  • CCR5 targeting agents are described in U.S. Patent Application Pub. Nos. 1 20180303830, 20170231991, 20140109245, and 20130303512; the disclosures of which are incorporated herein by reference in their entirety.
  • CCR5 antagonists such as but not limited to e.g., small molecule (including peptide and non-peptide small molecule) inhibitors, antibodies, and the like.
  • CCR5 antagonists include: Maraviroc (aka Selzentry or Celsentri), INCB-9471 ((4,6-dimethylpyrimidin-5-yl)-[4-[(3S)- 4-[(1R,2R)-2-ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl]-4- methylpiperidin-1-yl]methanone; orally available CCR5 antagonist; PubChem CID: 49871007), Leronlimab (PRO-140, a humanized monoclonal antibody directed against CCR5), Aplaviroc (4- (4- ⁇ [(3R)-1-butyl-3-[(R)-cycl
  • the active agent is an antibody that binds to CCR5.
  • An antibody that specifically binds to CCR5 can be polyclonal or monoclonal antibody or fragments that are sufficient to bind CCR5.
  • the antibody fragments can be, for example, monomeric Fab fragments, monomeric Fab' fragments, or dimeric F(ab)'2 fragments, single-chain antibody molecules (scFv) or humanized or chimeric antibodies produced from monoclonal antibodies by replacement of the constant regions of the heavy and light chains to produce chimeric antibodies or replacement of both the constant regions and the framework portions of the variable regions to produce humanized antibodies.
  • An antibody that specifically binds to CCR5 can be a humanized monoclonal antibody, such as Leronlimab (PRO 40), PA14, 2D7, RoAb13, RoAb14, 45523.
  • CCR5 antibodies are described by the reference Olson et al. Curr Opin HIV AIDS, 2009 March;4(2):104–111, which is herein incorporated by reference in its entirety.
  • the active agent is Leronlimab.
  • the active agent is a small molecule inhibitor of CCR5, such as but not limited to: Maraviroc, vicriviroc, aplaviroc, SCH-C, or TAK-779.
  • CCR5 targeting agents are described in U.S. Patent Application Pub.
  • Useful drugs targeting CCR5 may, in some instances, include CCR5 antagonists, such as but not limited to e.g., small molecule (including peptide and non-peptide small molecule) inhibitors, antibodies, and the like.
  • CCR5 antagonists include: Maraviroc (aka Selzentry or Celsentri), INCB-9471 ((4,6-dimethylpyrimidin-5-yl)-[4-[(3S)-4-[(1R,2R)-2-ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H- inden-1-yl]-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl]methanone; orally available CCR5 antagonist; PubChem CID: 49871007), Leronlimab (PRO-140, a humanized monoclonal antibody directed against CCR5), Aplaviroc (4-(4- ⁇ [(3R)-1-butyl-3-[(R)- cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9- yl]methyl ⁇ phenoxy)benzoic acid; a potent noncom
  • CCR5 antagonists are also illustrated by Singh and Chauthe, (Singh I P, Chauthe S K. Small molecule HIV entry inhibitors: Part I. Chemokine receptor antagonists: 2004-2010. Expert Opin Ther Pat.2011; 21(2):227-69), Ness et al., (Ness T L, Kunkel S L, Hogaboam C M. CCR5 antagonists: the answer to inflammatory disease? Expert Opin Ther Pat.2006; 16(8):1051-65) and Yang and Rotstein, (Yang H, Rotstein D M. Novel CCR5 antagonists for the treatment of HIV infection: a review of compounds patented in 2006-2008.
  • the CCR5 antagonist is selected in the group consisting of aryl oxime- piperazine derivatives (see, e.g., U.S. Pat. Nos. 6,689,783; and 7,247,631; and U.S. patent publication Nos.2005/0065319, and 2011/0059154), piperazine derivatives (see, e.g., U.S. Pat. No.6,689,765), piperidine derivatives (see, e.g., U.S. Pat. Nos.6,602,885; and 7,247,631; and U.S.
  • the CCR5 antagonist is a oxime piperazine derivative of the following formula: wherein: X is-selected from the group consisting of H; F; Cl; Br; I; —CF3; —CF3O; —CN; CH3SO2— ; and CF3SO2—; R 1 is H; straight chain alkyl or a branched alkyl; fluoro-C1-C6 alkyl; a C1-C6 alkylene carrying a C3-C7 cycloalkyl (for example, cyclopropylmethyl); —CH 2 CH 2 OH; —CH 2 CH 2 —O—(C 1 -C 6 )alkyl; —CH 2 C(O)—O—(C 1 —C 6 )alkyl; —CH 2 C(O)NH 2 ; —CH 2 C(O)—NH(C 1 -C 6 )alkyl; or —CH 2 C(O)—N((C 1 -C 6
  • the CCR5 antagonist is selected from one of the following compounds:
  • the CCR5 antagonist is of the following formula: or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted phenyl, pyridyl, thiophenyl or naphthyl;
  • R 1 is hydrogen or alkyl;
  • R 2 is substituted phenyl, substituted heteroaryl, naphthyl, fluorenyl, diphenylmethyl or optionally substituted phenyl- or heteroaryl-alkyl;
  • R 3 is hydrogen, alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, or optionally substituted phenyl, phenylalkyl, naphthyl, naphthylalkyl, heteroaryl or heteroarylalkyl;
  • R 4 , R 5 and R 7 are hydrogen or alkyl;
  • R 6 is hydrogen, alkyl or alkenyl.
  • the CCR5 antagonist is of the following formula: or a pharmaceutically acceptable salt thereof, wherein (1) R a is R 6a -phenyl, R 6a -pyridyl, R 6a -thiophenyl or R 6 -naphthyl; R 1 is hydrogen, C 1 -C 6 alkyl or C 2 -C 6 alkenyl; R 2 is R 7 , R 8 , R 9 -phenyl; R 7 , R 8 , R 9 -substituted 6-membered heteroaryl; R 7 , R 8 , R 9 - substituted 6-membered heteroaryl N-oxide; R 10 , R 11 -substituted 5-membered heteroaryl; naphthyl; fluorenyl; R 3 is R 10 -phenyl, pyridyl, pyrimidyl, pyrazinyl or thiazolyl; R 4 is hydrogen, C 1 -C 6 alkyl
  • the CCR5 antagonist is a pyrrolidine of the following formula: wherein: R 1 is selected from: (1) —CO 2 H, (2) —NO 2 , (3) -tetrazolyl, (4) -hydroxyisoxazole, (5) —SO 2 NHCO—(C 0-3 alkyl)-R 9 , wherein R 9 is independently selected from hydrogen, C 1- 6 alkyl, C 5-6 cycloalkyl, benzyl or phenyl, wherein alkyl, cycloalkyl, benzyl or phenyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, C 1-3 alkyl, —O—C 1-3 alkyl and trifluoromethyl, and (6) —P(O)(OH) 2 ; j is an integer which is 0, 1, 2 or 3; R 2 is hydrogen or C 1-6 alkyl; Q is —(CH 2 ) 1-3 —, —CH 2 OCH
  • the CCR5 antagonist is a compound selected from one of the following compounds: (2R)-[(3R,4S)-3- ⁇ [3-exo-(1H-Benzimidazo-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]methyl ⁇ -4-(3- fluorophenyl)pyrrolidin-1-yl](cyclohexyl)ethanoic acid; (2R)-Cyclohexyl((3S,4R)-3-(3-fluorophenyl)-4- ⁇ [3-exo-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]methyl ⁇ pyrrolidin-1-yl)ethanoic acid; (2R)-Cyclohexyl[(3R,4S)-3- ⁇ [3-exo-(2-ethyl-1H-benzimidazol-1-yl)-8-azabicyclo
  • the CCR5 antagonist is an anilide derivative of the following formula: Wherein: R 1 is an optionally substituted 5- to 6-membered ring; the ring A is an optionally substituted 6- to 7-membered ring; the ring B is an optionally substituted benzene ring; n is an integer of 1 or 2; Z is a chemical bond or a divalent group; R 2 is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammonium, (3) a group binding through a sulfur atom or (4) a group of the formula: wherein k is 0 or 1, and when k is 0, a phosphorus atom may form a phosphonium; and R 5 and R 6 are independently an optionally substituted hydrocarbon group,
  • the CCR5 antagonist is a compound selected from: N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-propoxyphenyl)-1,1-dioxo-2,3- dihydro-1-benzothiepine-4-carboxamide, 7-(4-butoxyphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-1,1-dioxo-2,3- dihydro-1-benzothiepine-4-carboxamide, 7-[4-[N-methyl-N-(2-propoxyethyl)amino]phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4- yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzo
  • the CCR5 antagonist is a bis-acridine derivative of the following formula: wherein: X1, X2, X3 and X4 are independently one or more of H, OR′, or halo; R′ is H or optionally substituted C1-6alkyl; R1 is H, C1-6alkyl, or one of R1 is —CO(CF3); n is 1 or 2; and R is H or C1-6alkyl.
  • the CCR5 antagonist is a compound selected from one of the following compounds: N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-1,2-ethanediamine bis(trifluoroactate); N,N′di-9-acridinyl-1,2-ethanediamine bis(trifluoroactate); N,N′-bis(6-chloro-2-methoxy-9-acridinyl)-1,3-propanediamine bis(trifluoroactate); 9,9′-(1,4-piperazinediyl)bis[6-chloro-2-methoxy-acridine]bis(trifluoroacetate); N-(6-chloro-2-methoxy-9-acridinyl)-N′-(6-chloro-2-hydroxy-9-acridinyl)-1,2-ethanediamine bis(trifluoroacetate); N,N′-bis(6-chloro-2-hydroxy-9-acridinyl)-1
  • the CCR5 antagonist is an benzanilide derivative selected from one of the following compounds: N-[3-(3-Dimethylamino)propoxy-4-methoxyphenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)- (1,1′-biphenyl)-4-carboxamide; N-[3-(2-Piperidine)ethoxy-4-methoxyphenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1′- biphenyl)-4-carboxamide; N-[3-(3-Dimethylaminopropyl)-4-methoxyphenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3- yl)biphenyl-4-carboxamide oxalate; N-[3-(1-Methyl-4-piperidyl)-4-methoxypheny
  • the CCR5 antagonist is a fused-ring pyridine derivative of the following formula: Wherein: R 1 is a 5- or 6-membered ring which may be substituted; R 3 is a hydrogen atom, a lower alkyl group which may be substituted or a lower alkoxy group which may be substituted; Z 1 is a 5- or 6-membered aromatic ring which may be further substituted; Z 2 is a group represented by -Z 2a -W 1 -Z 2b - wherein Z 2a and Z 2b are each O, S(O)m (wherein m is 0, 1 or 2), a substituted imino group, or a bond; and W 1 is an alkylene chain which may be substituted, an alkenylene chain which may be substituted, or a bond; n is 2; Y is or NR 4 (wherein R 4 is a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or an acyl group
  • the CCR5 antagonist is a benzazepine derivative of the following formula:
  • R 1 is a 5- or 6-membered aromatic ring which has a substituent represented by formula R- Z 1 -X 1 -Z 2 - (wherein, R is a hydrogen atom or an optionally substituted hydrocarbon group, X 1 is an optionally substituted alkylene chain, Z 1 and Z 2 are independently a heteroatom,) and may have a further substituent, the group represented by R may bind to said 5- or 6-membered aromatic ring to form a ring;
  • R 2 is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group or a halogen atom;
  • Y is an optionally substituted imino group;
  • ring A and ring B are independently an optionally substituted aromatic ring; and
  • W is a group represented by formula —W 1 —X 2 —W 2 — (wherein, W 1 and W 2 are independently
  • the CCR5 antagonist is a compound selected from: ( ⁇ )-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]- 2,3-dihydro-1-benzazepine-4-carboxamide; ( ⁇ )-7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]- 2,3-dihydro-1-benzazepine-4-carboxamide; ( ⁇ )-7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3- ylmethylsulfinyl)phenyl]-2,3-dihydro-1
  • R 1 is selected from hydrogen, deuterium, and C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with R 2 ;
  • L1 is selected from C1-6 alkylene, C3-10 cycloalkylene, C6-10 arylene, C5-12 heteroarylene, and 3- to 10-membered heterocyclylene;
  • L2 is absent or selected from —NH—, C2-6 alkylene, C2-6 alkenylene, —(C1-6 alkyleneoxy)y1- (C1-6 alkyleneoxy)y2-, C3-10 cycloalkylene, C6-10 arylene, C5-12 heteroarylene and 3- to 10-membered heterocyclylene; said —NH—, C2-6 alkylene, C2-6 alkenylene, C3-10 cycloalkylene, C6-10 arylene, C5- 12 heteroarylene, and 3- to 10-membered heterocyclylene are optionally substituted with one or more substituents independently selected from hydrogen, deuterium, halogen
  • the CCR5 antagonist is a 1-(3-aminopropyl) substituted cyclic amine derivative of the following formula: wherein: W is absent or —CH 2 CH 2 —; X is N or CR 6 ; R 1 is selected from a 5 to 7-membered heteroaryl unsubstituted or substituted with 1-3 substituents, wherein said heteroaryl contains 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen and each of said substituents is independently selected from a halogen, a C1-C4 straight or branched alkyl, a C1-C4 straight or branched haloalkyl, a C1-C4 straight or branched alkyloxy, a C1-C4 straight or branched haloalkoxy, —NR 10 R 11 , —C( ⁇ O)R 12 , a C1-C4 straight or branched alkanoyloxy, a cyano, a nitro and
  • the CCR5 antagonist is a heterocyclic derivative (see, e.g., U.S. patent publication No.2008/0299132; and WO2005/075484, and WO2005/121145).
  • the CCR5 antagonist is selected from one of the following formulae: Wherein: Ar is phenyl, 3-fluorophenyl, 3-chlorophenyl or 3,5-difluorophenyl; R 1 is selected from the group consisting of: wherein R a is hydrogen, —OH, —NMeCH2CONH2 or —OCMe2CONH2; b wherein R is hydrogen or cyano; and, c wherein R is 6-trifluoromethylpyridazin-3-yl, pyrimidin-5-yl, 5-trifluoromethyl-pyridin-2-yl; R 2 is selected from the group consisting of cyclopentyl, 2-carboxy-cyclopentyl, 3-oxo- cyclopentyl,
  • the CCR5 antagonist is selected from one of the following compounds: 4,4-Difluoro-cyclohexanecarboxylic acid ⁇ (S)-3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl ⁇ -amide; (S)-5-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3-(tetrahydro- pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one; 3,3-Difluoro-cyclobutanecarboxylic acid [(S)-3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)- hexahydro-pyrrolo[3,4-c]pyrrol-2-y
  • the CCR5 antagonist is a nitrogen-containing heterocyclic derivative as disclosed in U.S. patent publication No.2006/0178399.
  • the CCR5 antagonist is one of the following compounds: N-[4-(4- ⁇ [4-(butyl ⁇ [(2,4-difluorophenyl)amino]carbonyl ⁇ amino)-1- piperidinyl]methyl ⁇ phenoxy)phenyl]methanesulfonamide; N-[4-(4- ⁇ [4-(butyl ⁇ [(6-methyl-3-pyridinyl)amino]carbonyl ⁇ amino)-1- piperidinyl]methyl ⁇ phenoxy)phenyl]methanesulfonamide; N-[4-(4- ⁇ [4-(butyl ⁇ [(2,4-difluorophenyl)amino]carbonyl ⁇ amino)piperidin-1-yl]methyl ⁇ -3,5-dimethyl- 1H-pyra
  • the CCR5 antagonist is a triazaspiro[5.5]undecane derivative (see, e.g., U.S. patent publication No.2005/0267114).
  • the CCR5 antagonist is selected from one of the following compounds: (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminocarbonyl-2- chlorophenoxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane; (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(5-oxo-4,5-dihydro-1,2,4- thiadiazol-3-yl)phenoxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane; (3R)-1-butyl-2,5-di
  • the CCR5 antagonist is a heterocyclic derivative as disclosed in U.S. patent publication No. US20090131403.
  • the CCR5 antagonist is selected from one of the following compounds: N-(3-fluorophenyl)-N- ⁇ 1-[(6- ⁇ 4-[(4-methyl-1-piperazinyl)sulfonyl]phenoxy ⁇ -3-pyridinyl)methyl]-4- piperidinyl ⁇ -N′-(6-methyl-3-pyridinyl)urea; 4-[(5- ⁇ [4-((3-fluorophenyl) ⁇ [(6-methyl-3-pyridinyl)amino]carbonyl ⁇ amino)-1-piperidinyl]methyl ⁇ -2- pyridinyl)oxy]-N-(2-methoxyethyl)benzenesulfonamide; N-(3-fluorophenyl)-N′-(6-methyl-3-pyridinyl)-
  • the CCR5 antagonist is a peptide.
  • the CCR5 antagonist is all D: TTNYT (SEQ ID NO: ##) , which is derived from the CCR5 antagonist DAPTA (SEQ ID NO: ##) (Polianova M T, Ruscetti F W, Pert C B, Ruff M R.
  • Chemokine receptor-5 (CCR5) is a receptor for the HIV entry inhibitor peptide T (DAPTA). Antiviral Res 2005; 67:83-92).
  • the CCR5 antagonist is a cyclic amine compound as disclosed in U.S. patent publication No. 2003/0114443.
  • the CCR5 antagonist is selected from one of the following compounds: N-(3,4-Dichlorophenyl)-1-(methylsulfonyl)-N- ⁇ 3-[4-( ⁇ 4-[(methylsulfonyl)amino]phenyl ⁇ sulfonyl)-1- piperidinyl]propyl)-4-piperidinecarboxamide or a salt thereof; N-(3-Chlorophenyl)-1-(methylsulfonyl)-N-(3- ⁇ 4-[4-(methylsulfonyl)benzyl]-1-piperidinyl ⁇ propyl)-4- piperidinecarboxamide or a salt thereof; N-(3- ⁇ 4-[4-(Aminocarbonyl)benzyl]-1-piperidinyl ⁇ propyl)-N-(3,4-dichlorophenyl)-1- (methylsulfonyl)-4-piperidinecarboxamide or a salt thereof;
  • CCR5 antagonist examples include but are not limited to the compounds disclosed in WO00/166525, WO00/187839, WO02/076948, WO02/079156, WO2002070749, WO2003080574, WO2003042178, WO2004056773, WO2004018425, WO97/024325, WO 98/25617, WO98/025604, WO98/002151, WO01/90106, WO98/004554, WO99/17773, WO99/32100, WO00/06085, WO00/06146, WO00/10965, WO00/06153, WO00/21916, WO00/37455, EP1013276, WO00/38680, WO00/39125, WO00/40239, WO00/42045, WO00/53175, WO00/42852, WO00/66551, WO00/66558, WO00/66559, WO00
  • the CCR5 antagonists is selected from maraviroc (4,4-difluoro-N- ⁇ (1S)-3-[3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8- yl]-1-phenylpropyl ⁇ cyclohexanecarboxamide) and derivatives such as those described in (WO 00/38680; U.S. Pat.
  • the CCR5 antagonist may consist in a modified chemokines that can partially or completely block CCR5 activation.
  • Said modified chemokines CCR5 antagonists are well-known as illustrated by Ness et al., (2006), U.S. Pat. No.6,555,105 and U.S. Pat. No. 6,942,852.
  • Non-limiting examples of modified chemokines CCR5 antagonists include methiolynated RANTES (Met-RANTES), aminooxypentane-RANTES (AOP-RANTES), N ⁇ -(n-nonanoyl)-des- Ser 1 -RANTES (NNY-RANTES) and N ⁇ -(n-nonanol)-des-Ser 1 [L-thioproline 2 , L- ⁇ -cyclohexyl- glycine 3 ]-RANTES (PSC-RANTES) (Ness et al., 2006).
  • the active agent is an antibody that binds to CCR5.
  • An antibody that specifically binds to CCR5 can be polyclonal or monoclonal antibody or fragments that are sufficient to bind CCR5.
  • the antibody fragments can be, for example, monomeric Fab fragments, monomeric Fab' fragments, or dimeric F(ab)'2 fragments, single-chain antibody molecules (scFv) or humanized or chimeric antibodies produced from monoclonal antibodies by replacement of the constant regions of the heavy and light chains to produce chimeric antibodies or replacement of both the constant regions and the framework portions of the variable regions to produce humanized antibodies.
  • An antibody that specifically binds to CCR5 can be a humanized monoclonal antibody, such as Leronlimab (PRO 40), PA14, 2D7, RoAb13, RoAb14, 45523.
  • CCR5 antibodies are described by the reference Olson et al. Curr Opin HIV AIDS, 2009 March;4(2):104–111, which is herein incorporated by reference in its entirety.
  • the active agent is Leronlimab.
  • Non-limiting examples of antibody-based CCR5 antagonists include CCR5 mAb004, PRO 140 (Biswas P, Tambussi G, Lazzarin A. The status of co-receptor inhibition to counter HIV entry. Expert Opin Pharmacother. 2007; 8(7):923-33), HGS004 and HGS101 (Latinovic O, Reitz M, Le N M, Foulke J S, Desitkenheuer G, Lehmann C, Redfield R, Heredia A.
  • CCR5 antibodies HGS004 and HGS101 preferentially inhibit drug-bound CCR5 infection and restore drug sensitivity of Maraviroc-resistant HIV-1 in primary cells.
  • Virology. 2011; 411(1):32-40 2D7, PA9, PA14, MC-1, MC-4, MC-6, RoAb12, RoAb14, RoAb18 (Lopalco L. Natural anti-CCR5 antibodies in HIV-infection and -exposure. J Transl Med. 2011; 9 Suppl 1:S4) and those described in Briihl et al. (Briihl H, Cihak J, Stangassinger M, Schlondorff D, Mack M.
  • the CCR5 antagonist is a compound identified by an appropriate screening method.
  • the CCR5 antagonist is selected by a screening method that measures the residence time of the compound on CCR5, and the CCR5 antagonist is selected as compounds having long residence time, as compared to a standard (see, e.g., U.S. patent publication No.2004/0023845).
  • Tests and assays for screening and determining whether a candidate compound is a CCR5 antagonist are well known in the art (Ness et al., 2006, U.S. Pat. No.7,65,905, U.S. application Ser. No.09/834,996).
  • In vitro and in vivo assays may be used to assess the potency and selectivity of the candidate compounds to reduce CCR5 activity.
  • said candidate compound may be assayed for their ability to compete with the natural ligands of CCR5 for receptor binding.
  • a high throughput screen utilizing a CCR5 membrane binding assay identifies inhibitors of CCL5 (RANTES) binding.
  • the active agent targets CCL5/RANTES.
  • an inhibitor of CCL5/RANTES is employed as the active agents, where inhibitors of interest include, but are not limited to: small molecules, nucleic acids, specific binding members for CCL5/RANTES, such as an antibody, aptamer, or a peptide, etc., such as described above.
  • An example of an inhibitor of CCL5/RANTES is Met-CCL5.
  • Further examples of RANTES/CCL5 inhibitors that may be employed in embodiments of the invention include, but are not limited to, those described in United States Published Application Publication Nos. 20050220790, 20060165650, 20090148455, 20120077733, 20120201826, 20140377278, and 20150079099, the disclosures of which are herein incorporated by reference.
  • the CCL5 antagonist is an antibody that specifically binds to CCL5.
  • the antibody is at least one of: a polyclonal antibody, a monoclonal antibody, an intracellular antibodies, an antibody fragment, a single chain antibody (scFv), a heavy chain antibody, a synthetic antibody, a chimeric antibody, and humanized antibody.
  • the CCL5 inhibitor is an antisense nucleic acid.
  • the antisense nucleic acid is at least one of siRNA or miRNA.
  • the CCL5 inhibitor is at least one of: a chemical compound, a protein, a peptide, a peptidomimetic, a ribozyme, and a small molecule chemical compound.
  • the CCL5 antagonists include but are not limited to the compounds disclosed in U.S. patent publication Nos.2014/0377278, 2016/0175308 and 2007/0161550; and U.S. Pat No.10,940,132.
  • the CCL5 antagonist is a CCL5 polypeptide (see, e.g., U.S. patent publication No.2007/0161550), and a compound disclosed in Marques et al. (2013) Expert Opin Ther Targets 17(12):1439-60.
  • the CCL5 antagonist is a compound of the following formula: wherein: n and p are independently selected from 0 or 1; R1 and R2 are independently selected from H, OH, F, Cl, Br, I, (halogen)alkyl, C1-C8 straight or branched chain alkyl, C 1 -C 8 cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, optionally substituted C 1 -C 8 alkenyl, optionally substituted C 1 -C 8 alkynyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted heteroaryl, optionally substituted alkylheteroaryl, O-alkyl, O-cycloalkyl, O-alkylcycloalkyl, O-aryl, O-optionally substituted aryl, alkyl- O-aryl, alkyl-O-optionally substituted aryl, C(O)-aryl, C(O)-ary
  • the CCL5 antagonist is a compound that is an antagonist of a CCL5 receptor.
  • the CCL5 antagonist is an antagonist of a receptor selected from CCR1, CCR3, CCR4, CCR5 and GPR75.
  • the CCL5 antagonist is selected from cenicriviroc, GW873140, INCB009471, TBR 652, maraviroc, GSK706769, vicriviroc, SCH 417690, HGS1025, CCX 354-C, BAY86-5047, ZK811752, SH T 04268H, AZD4818, CP-481,715, GW766944, SB-728, lentivirus vector rHIV7-shI-TAR-CCR5RZ, and CCR5delta32 hematopoietic stem cell.
  • the CCL5 antagonist is an antibody selected from NI-0701, PRO 140, and CCR5mAb004. In certain cases, the CCL5 antagonist is an antagonist of the CCR5 receptor. In certain cases, the CCL5 antagonist is a CCR5 antagonist as described herein.
  • active agents may be administered to a subject as a pharmaceutical composition.
  • Pharmaceutical compositions formulated for topical administration may include ointments, lotions, creams, gels, drops, sprays, liquids, salves, sticks, soaps, aerosols, and powders. Any conventional pharmaceutical excipient, such as carriers, aqueous, powder or oily bases, thickeners and the like may be used.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will, in general, also contain one or more emulsifying, dispersing, suspending, thickening or coloring agents.
  • Powders may be formed with the aid of any suitable powder base.
  • Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing, solubilizing or suspending agents. Aerosol sprays are conveniently delivered from pressurized packs, with the use of a suitable propellant.
  • active agent compositions may be administered according to any desired dosage, such as once per day, a few or several times per day, or even multiple times per day, depending upon, among other things, the indication being treated and the judgment of the prescribing physician.
  • compositions that include one or more active agents may be administered once per day, a few or several times per day, or even multiple times per day, depending upon, among other things, the indication being treated and the judgment of the prescribing physician.
  • methods of administration may be chosen depending also on the condition being treated and the pharmaceutical composition being administered.
  • Administration of an effective amount (in one or multiple doses) of the subject agent(s) can be done in a variety of ways, including, but not limited to, subcutaneously, intravenously, intraperitoneally, intramuscularly, and direct injection to specified organs or tumors, systemic administration, etc.
  • Administration of the pharmaceutical compositions may be through a single route or concurrently by several routes.
  • the active agent can be administered to a subject via a suitable route of administration and include oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intra-arterial, intraperitoneal), or transdermal.
  • active agent is an anti-CCR5 antibody, such as Leronlimab (PRO 140).
  • the antibody active agent is administered with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers may include but are not limited to aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, saline, and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases, and the like.
  • the dose of the composition of the invention will vary depending on the subject and upon the particular route of administration used. Dosages can range from 0.1 g/kg to 100,000 g/kg.
  • the antibody or binding fragment thereof is formulated to deliver between 100 mg/mL to 200 mg/mL of the antibody or binding fragment thereof to the subject. In another embodiment the antibody or binding fragment thereof is formulated to deliver between 100 mg/mL to 150 mg/mL of the antibody or binding fragment thereof to the subject. In another embodiment the antibody or binding fragment thereof is formulated to deliver between 150 mg/mL to 200 mg/mL of the antibody or binding fragment thereof to the subject. In another embodiment the antibody or binding fragment thereof is formulated to deliver 175 mg/mL of the antibody or binding fragment thereof to the subject. Based upon the composition, the dose can be delivered continuously, such as by continuous pump, or at periodic intervals, e.g., on one or more separate occasions.
  • Desired time intervals of multiple doses of a particular composition can be determined without undue experimentation by one skilled in the art.
  • the antibody or binding fragment thereof is administered to the subject a plurality of times, and each administration delivers from 0.01 mg per kg body weight to 50 mg per kg body weight of the antibody or binding fragment thereof to the subject.
  • each administration delivers from 0.05 mg per kg body weight to 25 mg per kg body weight of the antibody or binding fragment thereof to the subject.
  • each administration delivers from 0.1 mg per kg body weight to 10 mg per kg body weight of the antibody or binding fragment thereof to the subject.
  • each administration delivers from 0.5 mg per kg body weight to 5 mg per kg body weight of the antibody or binding fragment thereof to the subject.
  • each administration delivers from 1 mg per kg body weight to 3 mg per kg body weight of the antibody or binding fragment thereof to the subject. In another embodiment, each administration delivers about 2 mg per kg body weight of the antibody or binding fragment thereof to the subject.
  • the antibody or binding fragment thereof is administered in a formulation comprising 175 mg/mL of the anti-CCR5 binding agent and may be delivered in two 1 mL shots for administration of about 350 mg in total to a subject in need thereof.
  • the antibody or binding fragment thereof is administered a plurality of times, and a first administration is separated from the subsequent administration by an interval of less than one week. In another embodiment, the first administration is separated from the subsequent administration by an interval of at least one week.
  • the first administration is separated from the subsequent administration by an interval of one week. In another embodiment, the first administration is separated from the subsequent administration by an interval of two to four weeks. In another embodiment, the first administration is separated from the subsequent administration by an interval of two weeks. In a further embodiment, the first administration is separated from the subsequent administration by an interval of four weeks. In yet another embodiment, the antibody or binding fragment thereof is administered a plurality of times, and a first administration is separated from the subsequent administration by an interval of at least one month. In a further embodiment, the antibody or binding fragment thereof is administered to the subject via intravenous infusion. In another embodiment, the antibody or binding fragment thereof is administered to the subject via subcutaneous injection. In another embodiment, the antibody or binding fragment thereof is administered to the subject via intramuscular injection.
  • dose levels can vary as a function of the specific compound, e.g., small molecule, antibody, nucleic acid, etc., the nature of the delivery vehicle, and the like.
  • Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means.
  • an effective amount of an active agent is administered to the adult mammal, the amount or dosage is effective when administered for a suitable period of time so as to evidence a reduction in one or more symptoms of the target disease.
  • an effective amount or dose of active agent will not only slow or halt the progression of the disease condition but will also induce the reversal of the condition, i.e., will cause an improvement the subject’s condition.
  • an “effective amount” or “effective dose” of active agent is meant an amount of active agent that will inhibit, antagonize, decrease, reduce, or suppress by about 20% or more, e.g., by 30% or more, by 40% or more, or by 50% or more, in some instances by 60% or more, by 70% or more, by 80% or more, or by 90% or more, in some cases by about 100%, i.e., to negligible amounts, and in some instances reverse, one or more target symptoms of the disease condition.
  • methods of treating a subject for a hypercytokinemia disease include methods of assessing the severity of a disease involving hypercytokinemia, such as methods of assessing as described below.
  • certain embodiments of the invention provide a method of assessing the severity of a disease involving hypercytokinemia in a subject, the method comprising:
  • hypercytokinemia is a potentially fatal immune reaction and involves a positive feedback loop between cytokines and immune cells, which causes in the body highly elevated levels of various cytokines.
  • Hypercytokinemia is also referenced as “cytokine storm.”
  • Hypercytokinemia typically involves increased concentration of cytokines, such as interferons, interleukins, chemokines, colony-stimulating factors, and tumor necrosis factors.
  • cytokines such as interferons, interleukins, chemokines, colony-stimulating factors, and tumor necrosis factors.
  • Such immune dysregulation can be an underlying factor in mortality resulting from many infections.
  • the disease involving hypercytokinemia further comprises an overproduction of immune cells and/or pro-inflammatory cytokines into the lungs of the subject.
  • Hypercytokinemia may result in excessive inflammatory response in the lungs, which typically occurs in the infections in the lungs or other organs.
  • Such excessive inflammatory response in the lung includes infiltration into the lungs by immune cells as well as excessive secretion of proinflammatory cytokines in the lungs, which in turn attracts more immune cells into the lungs.
  • hypercytokinemia can also involve positive-feedback loop between activated cells and released cytokines.
  • Assessing the severity of the disease may involve comparing the determined level of CCL5/RANTES in the test sample with the level of CCL5/RANTES in a control sample or a reference value.
  • a control sample can be obtained from one or more of the following: an individual belonging to the same species as the subject and not having the disease; an individual belonging to the same species as the subject and known to have the disease with known level of severity, for example, asymptomatic, mild, moderate, severe, or critical; or the subject prior to having the disease. If a control sample is obtained from a healthy individual and the level of CCL5/RANTES in the test sample is significantly higher than that of the control sample, particularly, higher than that of the control sample by: between 2 fold and 200 fold; between 10 fold and 150 fold, between 20 fold and 100 fold, or between 40 fold and 60 fold, the extent of the increase in the level of CCL5/RANTES in the test sample could be used to assess the severity of the disease in the subject.
  • an increase of between at least about 6 fold and at least about 20 fold in the CCL5/RANTES level in a test plasma sample compared to a control sample could indicate that the subject has a severe form of COVID-19; whereas, an increase of between at least about 60 fold and at least about 300 fold in the CCL5/RANTES level in a test plasma sample compared to a control sample could indicate that the subject has a critical form of COVID-19.
  • a person of ordinary skill in the art can determine the difference in the CCL5/RANTES level in a control sample and in a test sample that indicates different levels of severity of the disease.
  • the control sample and the test sample can be obtained from the same type of an organ or tissue.
  • the organ or tissue can be brain, eyes, pineal gland, pituitary gland, thyroid gland, parathyroid glands, thorax, heart, lung, esophagus, thymus gland, pleura, adrenal glands, appendix, gall bladder, urinary bladder, large intestine, small intestine, kidneys, liver, pancreas, spleen, stoma, ovaries, uterus, or skin.
  • the control sample and the test sample can also be obtained from the same type of a body fluid.
  • the body fluid can be aqueous humor, vitreous humor, bile, blood, cerebrospinal fluid, chyle, endolymph, perilymph, lymph, mucus, pericardial fluid, peritoneal fluid, pleural fluid, pus, rheum, saliva, sputum, synovial fluid, blood, serum or plasma.
  • a reference value corresponding to the level of CCL5/RANTES may indicate the level of CCL5/RANTES associated with severity of the disease, such as mild, moderate, severe, or critical form of a disease.
  • a reference value corresponding to level of CCL5/RANTES may represent the level of CCL5/RANTES in a subject who has mild, moderate, severe, or critical form of a disease.
  • the reference value can be: 200 pg/ml, 250 pg/ml; 300 pg/ml, 350 pg/ml or 400 pg/ml (which would indicate the absence of disease); or about: 1 ng/ml, 2 ng/ml, 3 ng/ml, 4 ng/ml, 5 ng/ml, 6 ng/ml, 7 ng/ml, 8 ng/ml, 9 ng/ml, 10 ng/ml (which would indicate severe form of COVID-19); or: 15 ng/ml, 20 ng/ml, 25 ng/ml, 30 ng/ml, 35 ng/ml, 40 ng/ml, 45 ng/ml, 50 ng/ml, 55 ng/ml, 60 ng/ml (which could indicate critical form of COVID-19).
  • CCL5/RANTES level in a test sample from a subject is 50 ng/ml, one could assess that the subject is suffering from or could develop a critical form of COVID-19.
  • CCL5/RANTES level in a test sample from a subject is 8 ng/ml, one could assess that the subject is suffering from or could develop a severe form of COVID-19.
  • CCL5/RANTES level in a test sample from a subject is 200 pg/ml, one could assess that the subject does not have COVID-19 or has asymptomatic or mild form of COVID-19.
  • a person of ordinary skill in the art can obtain appropriate reference values based on the disease being examined and such information can be obtained from the well-known sources in the relevant art or generated based on the testing conducted on a case by case basis.
  • the disease can be asymptomatic, mild, moderate, severe, or critical.
  • An asymptomatic form of COVID-19 does not show any symptoms in the subject.
  • a mild form of COVID-19 may show mild form of one or more of: tiredness, fever, cough, breathlessness after moderate exercise, sore throat, muscle ache, headache, and diarrhea. Mild form of COVID- 19 may not require management of symptoms.
  • a moderate form of COVID-19 may show moderate form of one or more of: tiredness, fever, cough, breathlessness after slight activity, sore throat, muscle ache, headache, and diarrhea.
  • Moderate form of COVID-19 may require managing the symptoms.
  • a severe form of COVID-19 may show of one or more of: severe tiredness, high fever, cough, breathlessness even at rest, painful breathing, loss of appetite, loss of thirst, sore throat, muscle ache, headache, diarrhea, and confusion.
  • Severe form of COVID- 19 would typically require significant intervention for managing symptoms, such as: pneumonia, hypoxemic respiratory failure, ARDS, sepsis, septic shock, cardiomyopathy, arrhythmia, acute kidney injury, and complications from prolonged hospitalization including secondary bacterial infections, thromboembolism, gastrointestinal bleeding, and critical illness polyneuropathy/myopathy.
  • a critical form of COVID-19 may show of one or more of: severe tiredness, high fever, cough, breathlessness even at rest, painful breathing, loss of appetite, loss of thirst, sore throat, muscle ache, headache, diarrhea, confusion, severe pneumonia, ARDS, sepsis, organ failure, coma, and death.
  • Critical form of COVID-19 requires hospitalization for managing symptoms such as: pneumonia, ARDS, sepsis, septic shock, cardiomyopathy, arrhythmia, acute kidney injury, and complications from prolonged hospitalization including secondary bacterial infections, thromboembolism, gastrointestinal bleeding, and critical illness polyneuropathy/myopathy. Ventilator assisted breathing may be required.
  • a disease involving hypercytokinemia can be an inflammatory disease or an infection.
  • An inflammatory disease can be an autoimmune disease, graft rejection, multiple sclerosis, pancreatitis, or multiple organ dysfunction syndrome.
  • a disease involving hypercytokinemia can also be an infection, such as a viral, bacterial, fungal, or parasitic infection. Additional examples of infections that can cause a disease involving hypercytokinemia are known in the art and severity of such diseases can be assessed according to the methods disclosed herein.
  • a bacterial infection can comprise bacteremia, bacterial sepsis, pneumonia, cellulitis, meningitis, erysipelas, infective endocarditis, necrotizing fasciitis, prostatitis, pseudomembranous colitis, pyelonephritis, or septic arthritis.
  • a bacterial infection can be caused by a Streptococcus spp., Staphylococcus spp., Salmonella spp., Pseudomonas spp., Clostridium spp., Vibrio spp., Mycobacterium spp. or Haemophilus spp. Additional examples of bacteria that can cause a disease involving hypercytokinemia are known in the art and severity of such bacterial infections can be assessed according to the methods disclosed herein.
  • a viral infection can be caused by a coronavirus, influenza virus, Epstein-Barr virus, Human Immunodeficiency Virus, Ebola virus, retrovirus, or variola virus.
  • the coronavirus can be severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2). Additional examples of viruses that can cause a disease involving hypercytokinemia are known in the art and severity of such viral infections can be assessed according to the methods disclosed herein.
  • a disease involving hypercytokinemia can also comprise ARDS, sepsis, SIRS, or toxic shock syndrome.
  • Any convenient method of determining CCL5/RANTES in a same may be employed, where various methods of determining CCL5/RANTES in a sample are known in the art and can be used in the methods disclosed herein. Certain such methods include flow cytometry, mass spectrometry, protein array analysis, Western blot analysis, enzyme-linked immunosorbent assay (ELISA), or radio-immune assay (RIA).
  • determining the level of CCL5/RANTES is performed by flow cytometry.
  • Flow cytometry is a methodology using multi-parameter data for identifying and distinguishing between different particle (e.g., bead) types i.e., particles that vary from one another in terms of label (wavelength, intensity), size, etc., in a fluid medium.
  • particle e.g., bead
  • label wavelength, intensity
  • size size, etc.
  • the particles in the sample are passed substantially one at a time through one or more sensing regions, where each of the cells is exposed separately and individually to a source of light at a single wavelength (or in some instances two or more distinct sources of light) and measurements of cellular parameters, e.g., light scatter parameters, and/or marker parameters, e.g., fluorescent emissions, as desired, are separately recorded for each cell.
  • the data recorded for each cell is analyzed in real time or stored in a data storage and analysis means, such as a computer, for later analysis, as desired.
  • particles e.g., beads
  • the energy source may include an illuminator that emits light of a single wavelength, such as that provided by a laser (e.g., He/Ne or argon) or a mercury arc lamp or an LED with appropriate filters.
  • a laser e.g., He/Ne or argon
  • a mercury arc lamp e.g., a mercury arc lamp
  • light at 488 nm may be used as a wavelength of emission in a flow cytometer having a single sensing region.
  • wavelengths of interest include, but are not limited to: 405nm, 535 nm, 561 nm, 635 nm, 642 nm, and the like.
  • the excited label emits fluorescence and the quantitative level of the polypeptide on each cell may be detected, by one or more fluorescence detectors, as it passes through the one or more sensing regions.
  • detectors In flow cytometry, in addition to detecting fluorescent light emitted from particles labeled with fluorescent markers, detectors, e.g., light collectors, such as photomultiplier tubes (or "PMT"), an avalanche photodiode (APD), etc., are also used to record light that mediated by, e.g., emitted by a label on, the particle.
  • Flow cytometers may further include one or more electrical detectors.
  • an electrical detector may be employed for detecting a disturbance caused by a particle passing through an electrical field propagated across an aperture in the path of the particles.
  • Such flow cytometers having electrical detectors will contain a corresponding electrical energy emitting source that propagates an electrical field across the flow path or an aperture through which cells are directed.
  • Any convenient electrical field and/or combination of fields with appropriate detector(s) may be used for the detection and/or measurement of particles passing through the field including but not limited to, e.g., a direct current electrical field, alternating current electrical field, a radio-frequency field, and the like.
  • Flow cytometers further include data acquisition, analysis and recording means, such as a computer, wherein multiple data channels record data from each detector for each cell as it passes through the sensing region.
  • the purpose of the analysis system is to classify and count cells wherein each cell presents itself as a set of digitized parameter values and to accumulate data for the sample as a whole.
  • the flow cytometry can comprise a bead-based assay, such as a sandwich protocol for bead based assay.
  • determining the level of CCL5/RANTES by flow cytometry comprises contacting the sample with a bead comprising an antibody that specifically binds to CCL5/RANTES, washing the bead and contacting the washed bead with a fluorescently labeled secondary antibody that specifically binds to CCL5/RANTES, washing the bead and detecting the presence of CCL5/RANTES on the bead by detecting by flow cytometry the label on the bead.
  • determining the level of CCL5/RANTES by flow cytometry comprises contacting the sample with a bead comprising an antibody that specifically binds to CCL5/RANTES, washing the bead and contacting the washed bead with a biotinylated secondary antibody that specifically binds to CCL5/RANTES, washing the bead and contacting the washed bead with a fluorescently labeled streptavidin, and detecting the presence of CCL5/RANTES on the bead by detecting by flow cytometry the fluorescent label on the bead.
  • the assay employed is BioLegend’s LEGENDplexTM bead-based immunoassay (BioLegend, San Diego, CA).
  • the fluorescent label used to detect the bead can be selected from a large number of dyes that are commercially available from a variety of sources, such as Molecular Probes (Eugene, OR) and Exciton (Dayton, OH).
  • fluorophores of interest include, but are not limited to, 4-acetamido-4'-isothiocyanatostilbene -2,2'disulfonic acid; acridine and derivatives such as acridine, acridine orange, acridine yellow, acridine red, and acridine isothiocyanate; 5-(2'- aminoethyl)aminonaphthalene-1 -sulfonic acid (EDANS); 4-amino-N-[3- vinylsulfonyl)phenyl]naphthalimide-3,5 disulfonate (Lucifer Yellow VS); N-(4-anilino-1- naphthyl)maleimide; anthranilamide
  • nucleic acid dyes or stains containing intrinsic fluorescence including those that specifically label DNA.
  • Dyes and stains that are specific for DNA (or preferentially bind double stranded polynucleotides in contrast to single- stranded polynucleotides) and therefore may be employed as non-specific stains include, but are not limited to: Hoechst 33342 (2'-(4-Ethoxyphenyl)-5-(4-methyl-1-piperazinyl)-1 H,1'H-2,5'- bibenzimidazole trihydrochloride) and Hoechst 33258 (4-[6-(4-Methyl-1 -piperazinyl)-1',3'-dihydro- 1 H,2'H-2,5'-bibenzimidazol-2 , -ylidene]-2,5-cyclohexadien-1-one trihydrochloride) and others of the Hoechst series; SYTO 40,
  • YOYO-1 propidium iodide
  • YO-PRO-3 TO-PRO-3
  • YOYO-3 and TOTO-3 SYTOX Green
  • SYTOX methyl green
  • acridine homodimer 7-aminoactinomycin D
  • 9-amino-6-chloro-2- methoxyactridine SYTOX Green
  • determining the level of CCL5/RANTES is performed by ELISA.
  • ELISA can be direct ELISA, indirect ELISA, competitive ELISA, or sandwich ELISA.
  • Various methods of conducting ELISA assay are known in the art and can be used in the methods disclosed herein.
  • An example of such an assay is the Quantikine® ELISA Human CCL5/RANTES Immunoassay (RnD Systems, Inc.).
  • certain embodiments of the invention provide a method comprising: assaying the level of CCL5/RANTES in a sample obtained from a subject suffering from a disease involving hypercytokinemia. Such methods can further comprise assaying the level of CCL5/RANTES in a control sample and/or obtaining one or more reference values corresponding to the level of CCL5/RANTES.
  • control samples and reference values discussed above are applicable to the methods of assaying CCL5/RANTES.
  • a sample for assaying the level of CCL5/RANTES can be obtained from a subject suffering from various diseases discussed above.
  • various methods discussed above could be used for assaying the level of CCL5/RANTES in a sample.
  • the methods of assaying the level of CCL5/RANTES in a sample obtained from a subject further comprises treating the subject for the disease.
  • Certain such embodiments comprise treating a subject by administering to the subject an inhibitor of CCL5/RANTES or an inhibitor of CCR5, e.g., as described above.
  • such disease is a severe or critical form of COVID-19.
  • Various therapeutic methods discussed above, particularly, various inhibitors of CCL5/RANTES or CCR5 discussed above can be used in the methods of treating a subject discussed herein. DEVICES FOR ASSAYING T HE LEVEL OF CCL5/RANTES
  • the device is a flow cytometer.
  • the flow cytometer can comprise a signal processing unit that is configured to indicate whether the level of CCL5/RANTES in a sample is above or below a predetermined threshold.
  • Such signal processing unit can comprise a physical computer-readable medium comprising instructions that, when executed, indicate whether the level of CCL5/RANTES in a sample is above or below a predetermined threshold.
  • the predetermined threshold for CCL5/RANTES level can be about: 200 pg/ml, 250 pg/ml, 300 pg/ml, 350 pg/ml, 400 pg/ml, 1 ng/ml, 2 ng/ml, 3 ng/ml, 4 ng/ml, 5 ng/ml, 6 ng/ml, 7 ng/ml, 8 ng/ml, 9 ng/ml, 10 ng/ml, 15 ng/ml, 20 ng/ml, 25 ng/ml, 30 ng/ml, 35 ng/ml, 40 ng/ml, 45 ng/ml, 50 ng/ml, 55 ng/ml, or 60 ng/ml.
  • the device comprises an internal control that provides a signal corresponding to the CCL5/RANTES level at the predetermined threshold. Accordingly, a signal intensity higher than that of the internal control would indicate that the level of CCL5/RANTES in the tested sample is higher than the predetermined threshold, whereas, a signal intensity lower than that of the internal control would indicate that the level of CCL5/RANTES in the tested sample is lower than the predetermined threshold.
  • the device is provided with a separate container containing a control having CCL5/RANTES at a concentration of the predetermined threshold.
  • Example 1 CCL5/RANTES levels in severe cases of COVID-19
  • This Example demonstrates that patients with severe COVID-19 have significantly reduced CDS T- effector cells and to a lesser extent CD4 T-helper cells.
  • the predominant cytokines in hypercytokinemia or cytokine storm including IL-1 ⁇ , IL-8, IL-6 were quantified in patients with severe COVID-19.
  • CCL5/RANTES is up regulated in severe COVID-19 patients to an extent much greater than the other molecules more commonly associated with COVID-19 infection. Because CCL5/RANTES contributes to the immunopathogenesis of COVID-19 lung disease and that CCL5/RANTES is involved in acute renal disease which is common in these patients, blocking CCL5/RANTES can be used to treat COVID-19, particularly, a severe form of COVID-19. 1.
  • cytokine storm cytokine storm
  • cytokines and chemokines were extremely variable at Day 0 in the 10 critical patients including the IL- 1b, IL-6, and IL-8 which are commonly associated with the cytokine storm (FIGS. 1A-1C).
  • CCL5/RANTES was significantly elevated in all patients (FIG. 1 D).
  • RANTES did not drop as abruptly, blockade of CCR5 by leronlimab as determined by receptor occupancy was close to 100% at day 7 in all patients.
  • Table 1 below provides representative normal cytokine levels.
  • Table 2 below provides cytokine levels from COVID-019 samples.
  • CCR5 blockade can prevent the migration of FoxP3+ t- regulatory cells (Tregs) into the tumor microenvironment. Similarly, CCR5 blockade may repolarize macrophages from pro- inflammatory cytokine including IL-6 producing M2 macrophages to anti-tumor M1 macrophages.
  • Tregs FoxP3+ t- regulatory cells
  • CCR5 blockade may repolarize macrophages from pro- inflammatory cytokine including IL-6 producing M2 macrophages to anti-tumor M1 macrophages.
  • T-cell exhaustion was first described in mice during chronic lymphocyte choriomeningitis virus (LCMV) infection and more recently in infections such as HCV and HBV as well as cancer. T-cell exhaustion though common in chronic infections has been demonstrated to occur as a function of antigen (viral) load (richter) and can occur in as little as 2 weeks. These data are consistent with the data presented in this report demonstrating persistent viral load over the first 7 days of treatment. Further evidence of T-cell exhaustion in the present study is the increased expression of T-cell exhaustion markers PD-1 and LAGS on both CD4 and CD8 T-cells. Following 7 days of leronlimab, the expression of PD-I and LAGS significantly decreases compared to Day 0. Interestingly, correlation of PD-1 and LAGS with liver function in these patients as reflected by decreased in liver transaminases.
  • LCMV chronic lymphocyte choriomeningitis virus
  • CCL5/RANTES has been demonstrated to cause acute renal failure and liver toxicity, both common findings in COVID-19 infection. All 10 of the patients in the current study has some degree of renal failure before administration of leronlimab.
  • CCR5 antagonists such as the small molecule CCR5 antagonists INCB-9471 , Aplaviroc, Vicriviroc, SCH-C, TAK-779, cencriviroc, OB-002, and BMS-813160 would also be effective in treating subjects for COVID-19.
  • a method of treating a subject for COVID-19 comprising: administering to the subject a CCR5/CCL5 interaction inhibitor to treat the subject for COVID-19.
  • a method of treating a subject for a critical or severe form of a disease involving hypercytokinemia comprising: administering to the subject a CCR5/CCL5 interaction inhibitor, wherein the subject is identified to have a higher level of CCL5/RANTES in a test sample obtained from the subject compared to a control sample or a reference value, to treat the subject for a mild, moderate, critical or severe form of a disease involving hypercytokinemia.
  • the disease involving hypercytokinemia further comprises an overproduction of immune cells and pro-inflammatory cytokines into the lungs of the subject.
  • the disease is an inflammatory disease or an infection.
  • the infection is a bacterial infection.
  • the bacterial infection comprises bacteremia, bacterial sepsis, pneumonia, cellulitis, meningitis, erysipelas, infective endocarditis, necrotizing fasciitis, prostatitis, pseudomembranous colitis, pyelonephritis, or septic arthritis.
  • coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • the disease comprises acute respiratory distress syndrome (ARDS), sepsis, systemic inflammatory response syndrome (SIRS), or toxic shock syndrome.
  • determining the level of CCL5/RANTES by flow cytometry comprises contacting the sample with a bead comprising an antibody that specifically binds to CCL5/RANTES, washing the bead and contacting the washed bead with a biotinylated secondary antibody that specifically binds to CCL5/RANTES, washing the bead and contacting the washed bead with a fluorescently labeled streptavidin, and detecting the presence of CCL5/RANTES on the bead by detecting by flow cytometry the fluorescent label on the bead.
  • bacterial infection comprises bacteremia, bacterial sepsis, pneumonia, cellulitis, meningitis, erysipelas, infective endocarditis, necrotizing fasciitis, prostatitis, pseudomembranous colitis, pyelonephritis, or septic arthritis.
  • ARDS acute respiratory distress syndrome
  • SIRS systemic inflammatory response syndrome
  • toxic shock syndrome ARDS
  • ARDS acute respiratory distress syndrome
  • SIRS systemic inflammatory response syndrome
  • determining the level of CCL5/RANTES is performed by flow cytometry, mass spectrometry, protein array analysis, Western blot analysis, enzyme-linked immunosorbent assay (ELISA), or radio-immune assay (RIA).
  • ELISA enzyme-linked immunosorbent assay
  • RIA radio-immune assay
  • determining the level of CCL5/RANTES by flow cytometry comprises contacting the sample with a bead comprising an antibody that specifically binds to CCL5/RANTES, washing the bead and contacting the washed bead with a biotinylated secondary antibody that specifically binds to CCL5/RANTES, washing the bead and contacting the washed bead with a fluorescently labeled streptavidin, and detecting the presence of CCL5/RANTES on the bead by detecting by flow cytometry the fluorescent label on the bead.
  • a method comprising: assaying the level of CCL5/RANTES in a sample obtained from a subject suffering from a disease involving hypercytokinemia.
  • the infection is a bacterial infection.
  • the bacterial infection comprises bacteremia, bacterial sepsis, pneumonia, cellulitis, meningitis, erysipelas, infective endocarditis, necrotizing fasciitis, prostatitis, pseudomembranous colitis, pyelonephritis, or septic arthritis.
  • coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • ARDS acute respiratory distress syndrome
  • SIRS systemic inflammatory response syndrome
  • toxic shock syndrome ARDS
  • determining the level of CCL5/RANTES by flow cytometry comprises contacting the sample with a bead comprising an antibody that specifically binds to CCL5/RANTES, washing the bead and contacting the washed bead with a biotinylated secondary antibody that specifically binds to CCL5/RANTES, washing the bead and contacting the washed bead with a fluorescently labeled streptavidin, and detecting the presence of CCL5/RANTES on the bead by detecting by flow cytometry the fluorescent label on the bead.
  • a device configured to indicate whether the level of CCL5/RANTES in a sample obtained from a subject suffering from a disease involving hypercytokinemia is above or below a predetermined threshold.
  • the device according to Clause 92 comprising an internal control that provides a signal corresponding to the CCL5/RANTES level at the predetermined threshold.
  • the predetermined threshold is 1 ng/ml.
  • a range includes each individual member.
  • a group having 1-3 articles refers to groups having 1 , 2, or 3 articles.
  • a group having 1-5 articles refers to groups having 1 , 2, 3, 4, or 5 articles, and so forth.

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Abstract

Sont prévues des méthodes de traitement d'un sujet atteint de la COVID-19. Des aspects des méthodes consistent à administrer au sujet une quantité efficace d'un inhibiteur de l'interaction CCR5/CCL5, tel qu'un antagoniste CCR5. Sont également prévues des méthodes d'évaluation de la gravité d'une maladie faisant intervenir une hypercytokinémie, telle que la COVID-19, en déterminant le niveau de CCL5/RANTES chez un sujet, ainsi que des compositions à utiliser dans de telles méthodes.
PCT/US2021/029096 2020-04-27 2021-04-26 Méthodes et compositions pour le traitement d'infections de type choc cytokinique, notamment la covd-19, par inhibition de l'interaction ccr5/ccl5 Ceased WO2021222069A1 (fr)

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PH1/2021/551739A PH12021551739A1 (en) 2020-04-27 2021-04-26 Methods of treating cytokine storm infections, including covid-19, by inhibiting ccr5/ccl5 (rantes) interaction, and compositions for practicing the same
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